Iontophoresis is a noninvasive technique, in which an electric current is used to enhance the penetration of charged drugs to a tissue.
Iontophoresis has been used in various fields of medicine, including transdermal administration of local anesthetics, testing for cystic fibrosis by transcutaneous delivery of pilocarpine, administration of vidarabine to patients with herpes orolabialis, fluoride administration to patients with hypersensitive dentin, and gentamicin administration for bacterial otitis.
Transcorneal or transscleral iontophoresis of various charged drugs have been reported. High levels of antibiotics were measured in the cornea and aqueous humor after transcorneal iontophoresis, compared with topical application or subconjunctival and intravenous injection which do not achieve adequate drug levels and involve other complications. Moreover, published data confirm that high drug concentrations penetrate also the posterior segments of the eye after transscleral iontophoresis, allowing the treatment of posterior disorders of the eye, such as posterior uveitis and endophthalmitis. These studies used iontophoresis of drug solution, which is technically clumsy, may cause mechanical injuries to the cornea and demands sterilization of the solution and cup before each treatment.
While iontophoresis has been developed for the eye, little attention was given to the damages that the iontophoresis can inflict to the eye.
In addition, in most reports, patents and patent applications, mentioned below, no distinction was made between the sites on the eye where the iontophoresis is applied. The following is summary of art related to the present invention:
U.S. Pat. No. 4,564,016 describes an iontophoretic device using a solution chamber where current flow is adjusted to a desired value by adjusting a potentiometer for a flow passage of a diameter of 0.25 to 0.5 millimeters, which is equivalent to a range of current density of 200 milliampere to 2000 milliamperes per cm2. This is a huge amount of current that may electrify the patient or at least cause a significant damage to the eye.
WO 91/12049 describes an iontophoretic system for focal transcleral destruction of living human tissue for the purpose of immediate decreasing eye pressure. A current of about 3.0-4.0 milliamperes for about 30 seconds to 5 minutes is applied in dozens locations on the sclera. The surface area that this apparatus is applied for is in the range of 0.2 to 2 mm, preferably 0.3-0.6 mm in diameter which translates to about 0.3 mm2 or a current of about 1200 milliampers per cm2.
Barza M, Peckman C, and Baum J. Ophthalmology. 1986 January; 93(1):133-9, describes transscleral iontophoresis of cefazolin, ticarcillin, and gentamicin in the rabbit. The authors applied 2 milliampers for 10 minutes and were able to achieve mean vitreal concentrations of cefazolin, ticarcillin, and gentamicin of 94-207 micrograms/ml in the normal rabbit eye. The current density applied onto the sclera, in this publication is 254 milliamperes/cm2. After 10 minutes of such application, no doubt that a high amount of drug is found in the inner parts of the eye as the process drilled a hole in the sclera.
Maurice D M, Ophthalmology. 1986 January; 93(1):128-32, describes iontophoresis of fluorescein into the posterior segment of the rabbit eye. As stated in the article, iontophoresis of appreciable quantities of fluorescein into the vitreous body of the rabbit results from the use of a high electrical current density (127-254 mA/cm2) over a limited area of the globe. This is achieved by passing current through the fluorescein when it is held against the region of the ora serrata in a tube less than 1 mm in diameter. The retina is destroyed over a corresponding area when the current enters the eye. Again, current density of over 100 milliamperes/cm2 was applied to the sclera and caused damage while inserting a high dose of drug.
WO 99/40967, to one of the present inventors, describes an invention, wherein drugs are delivered to the eye using solid hydrogel discs of a size of 3 millimeter in diameter applying onto the cornea a current of up to 1 milliamper which is translated to about 14 milliamperes/cm2.
It is clear from the art described above that very little attention was given to the adverse effect that the iontophoresis process might have on the tissue on which it is applied and on the long term undesired effects of such treatment. This is particularly surprising in relation to iontophoresis application to the eye, as the occular tissue is known to be particularly sensitive and vulnerable. Moreover, on the basis of the prior art one may apply a current as high as 2000 milliamperes per cm2 that may electrify the patient as well as the medical personnel applying the treatment. Also, no information is available on the sensitivity differences between different tissues, such as the eye versus other tissues, as well as between different portions of the eye.